Implantable prosthetic devices have been used in the surgical repair or replacement of internal tissue for many years. The efficacy of many types of implants is primarily dependent upon the surrounding tissue""s adaptive reformation around and ability to bond to the implant surface. In orthopedic implants in particular, the geometry and the quality of bone reformation determines how much load the bone can resist. Orthopedic implants include a wide variety of devices, each suited to fulfill particular medical needs. Examples of such devices are hip joint replacement devices, knee joint replacement devices, shoulder joint replacement devices, and pins, braces and plates used to set fractured bones. Some contemporary orthopedic implants, including hip and knee components, use high performance metals such as cobalt-chrome and titanium alloy to achieve high strength. These materials are readily fabricated into the complex shapes typical of these devices using mature metal working techniques including casting and machining.
At least two other methods are currently employed for bone and joint replacement and repair. Those methods include: (1) the use of grouting materials such as poly(methyl methacrylate) (PMMA) as bone cement between the bone and the prosthesis; and (2) direct opposition of bone tissue onto porous and non-porous implant surfaces. The latter method is known as the xe2x80x9ccementless implant method.xe2x80x9d
In one example of the cementless implant method, a prosthesis is coated with hydroxyapatite which is a major inorganic component of bone. The hydroxyapatite-coated prosthesis is then implanted in the bone cavity. The hydroxyapatite, which is a calcium salt, is believed to facilitate osteointegration with the bone tissues. After partial integration of the hydroxyapatite-coated prosthesis with the bone, layers of hydroxyapatite can be detected between the prosthesis and the bone tissues.
Despite the success of both metal and non-metal components in many patients, long term data has demonstrated an unacceptably high failure rate in more active patients due to loosening of the implant caused by bone resorption around the implant or failure to achieve bone ingrowth. Bone resorption results from stress shielding of the bone around the implant. The failure to achieve bone ingrowth into the surface of the implant to support implant mechanical stability has been a major problem with conventional implants. The metal orthopaedic prostheses rely on poly(methyl methacrylate) for attachment and fixation to bone. Loosening of such implants as a result of cement failure has resulted in additional surgeries for securing the implants. In order to avoid the problems associated with these prostheses, prostheses having porous or centered coatings have also been used. Although these materials encourage tissue ingrowth, the process of ingrowth occurs over a period of weeks to months, during which time the implant may be loosened and fail to function properly.
It has been discovered according to the present invention that conventional implants can be improved by coating with a layer of gold and attaching to the gold a bioactive molecule. The bioactive molecule functions at the implant surface to promote a favorable, local, environmental response. Accordingly, the invention is an improved implantable prosthetic device coated with a bioactive molecule.
The prosthetic device provided according to the invention is convenient and simple to prepare. The bioactive molecules are directly coupled to the prosthetic device surface through a gold-sulfide bond using simple solution chemistry techniques. Prior art methods for modifying the surface of biomaterials were complex and cumbersome. For instance, in order to conjugate a molecule to a polymeric surface, the surface would first have to be modified to add a functional group to which the molecule could bind. In some cases the molecule would require the addition of a linking group which is capable of reacting with the functional group.
According to one aspect, the invention is a prosthetic device including a shaped substrate having a substrate surface, for implantation in a mammal, a layer of gold attached to the substrate surface and defining a tissue contacting surface, and a bioactive molecule bound to the gold layer. The shaped substrate can be, for example, a polymer, a metal, a plastic, a fabric, a ceramic, a biological material, or a composite of two or more materials. The gold layer may be any thickness but preferably the gold layer has a thickness of about 10 to 1000 Angstroms. The bioactive molecule in turn can form a monolayer on the surface of the gold which, depending on the size of the bioactive molecule, is about 1 to 500 Angstroms in thickness.
The bioactive molecule can be virtually any molecule which can be attached to the gold layer and which can affect favorably the implant in its local environment once implanted. The bioactive molecule, therefore, can be natural or synthetic including a protein, a peptide, a protein analog, a sugar, a lipid, a glycol protein, a glycolipid or a nucleic acid. In one embodiment the bioactive molecule is selected from the group consisting of a cell modulating molecule, a chemotactic molecule, an anticoagulant moleucle, an antithrombotic molecule, an anti-tumor molecule, an anti-infectious molecule, a growth potentiating molecule, and an anti-inflammatory molecule. In one embodiment the cell modulating molecule is selected from the group consisting of an anti-integrin antibody, a bone morphogenic protein, an integrin binding protein, and a cadherin binding protein. In another embodiment the chemotactic molecule is an extracellular matrix molecule selected from the group consisting of collagen, fibronectin, laminin, and proetoglycan. In yet another embodiment the anti-tumor molecule is selected from the group consisting of methotrexate, adriamycin, cyclophosphamide, and taxol. The anti-infectious molecule is selected from the group consisting of antibiotics such as penicillin according to another embodiment. In another embodiment the growth potentiating molecule is selected from the group consisting of growth factors such as PDGF, EGF, FGF, TGF, NGF, CNTF, and GDNF. According to another embodiment the anti-inflammatory molecule is selected from the group consisting of steroidal and non-steroidal compounds.
The layer of gold can be attached directly to the substrate surface. In another embodiment the layer of gold is attached to the substrate surface via attachment to an intermediate layer, such as a layer of titanium intermediate the gold layer and the substrate surface.
According to another embodiment the surface of the prosthetic device is formed of a porous material, wherein the layer of gold creates a gold surface that has projections and indentations and wherein the layer of gold has an approximately uniform thickness across the surface of the porous material.
According to another aspect, the invention is a prosthetic device including a shaped substrate having a substrate surface, for implantation in a mammal, a layer of gold attached to the substrate surface and defining a tissue contacting surface, and a bioactive peptide bound to the gold layer. The shaped substrate can be, for example, a polymer, a metal, a plastic, a fabric, a ceramic, a biological material, or a composite of two or more materials. The gold layer may be any thickness but preferably the gold layer has a thickness of about 10 to 1000 Angstroms. The bioactive peptide forms a monolayer on the surface of the gold which, depending on the size of the peptide, is about 1 to 500 Angstroms in thickness.
The bioactive peptide can be any peptide which can be attached to the gold layer and which can affect favorably the implant in its local environment. It can be natural or synthetic. In one embodiment the bioactive peptide is selected from the group consisting of a cell modulating peptide, a chemotactic peptide, an anticoagulant peptide, an antithrombotic peptide, an anti-tumor peptide, an anti-infectious peptide, a growth potentiating peptide, and an anti-inflammatory peptide. In one embodiment the cell modulating peptide is selected from the group consisting of an anti-integrin antibody fragment, a cadherin binding peptide, a bone morphogenic protein fragment, and an integrin binding peptide. Preferably the cell modulating peptide is a integrin binding peptide which is selected from the group consisting of RGDC, RGEC, RGDT, DGEA, DGEAGC, EPRGDNYR, RGDS, EILDV, REDV, YIGSR, SIKVAV, RGD, RGDV, HRNRKGV, KKGHV, XPQPNPSPASPVVVGGGASLPEFXY, and ASPVVVGGGASLPEFX. The peptides also may be any functionally active fragment of the proteins disclosed herein as being bioactive molecules useful according to the invention. In another embodiment the chemotactic peptide is selected from the group consisting of functionally active fragments of collagen, fibronectin, laminin, and proteoglycan. In yet another embodiment the anti-tumor peptide is selected from the group consisting of functionally active fragments of protein anti-tumor agents. The anti-infectious peptide is selected from the group consisting of functionally active fragments of the protein anti-infectious agents according to another embodiment. In another embodiment the growth potentiating peptide is selected from the group consisting of functionally active fragments of PDGF, EGF, FGF, TGF, NGF, CNTF, GDNF, and type I collagen related peptides. According to another embodiment the anti-inflammatory peptide is selected from the group consisting of functionally active fragments of anti-inflammatory agents.
The layer of gold can be attached directly to the substrate surface. In another embodiment the layer of gold is attached to the substrate surface via attachment to an intermediate layer, such as a layer of titanium intermediate the gold layer and the substrate surface.
According to another embodiment the surface of the prosthetic device is formed of a porous material, wherein the layer of gold creates a gold surface that has projections and indentations and wherein the layer of gold has an approximately uniform thickness across the surface of the porous material.
The invention in another aspect is a prosthetic device including a shaped substrate formed of a textured material having a substrate surface with first projections and first indentations and a layer of gold attached to the substrate surface of the textured material, wherein the layer of gold creates a gold surface that has second projections and second indentations corresponding to the first projections and first indentations. In one embodiment, the layer of gold has an approximately uniform thickness across the substrate surface of the textured material. Preferably the textured material is a porous material such as a porous titanium material, a porous polymer, or any other non-fabric porous material.
In one embodiment the textured material is a polymer. In another embodiment the gold layer has a thickness of about 10 to 1000 Angstroms.
According to yet another embodiment the prosthetic device also includes a layer of bioactive peptide attached to the gold surface through a gold-sulfide bond.
In another aspect the invention is a prosthetic device including a shaped substrate having a substrate surface, a layer of gold attached to the substrate surface, and an RGDC peptide attached to the gold layer through a gold-sulfide bond. According to an embodiment the shaped substrate is a polymer, a metal, a plastic, a fabric, a ceramic, a biological material, or a composite of two or more materials. In one embodiment the gold layer has a thickness of about 10 to 1000 Angstroms. In another embodiment the bioactive peptide forms a layer about 1 to 500 Angstroms in thickness.
The layer of gold is attached directly to the substrate surface in one embodiment. In another embodiment the layer of gold is attached to the substrate surface via attachment to a layer of titanium intermediate the gold layer and the substrate surface.
According to another embodiment the surface of the prosthetic device is formed of a porous material, wherein the layer of gold creates a gold surface that has projections and indentations. In one embodiment the layer of gold has an approximately uniform thickness across the surface of the porous material.